Contribution of electromechanical coupling between K_V and Ca_V1.2 channels to coronary dysfunction in obesity

Previous investigations indicate that diminished functional expression of voltage-dependent K⁺ (K_V) channels impairs control of coronary blood flow in obesity/metabolic syndrome. The goal of this investigation was to test the hypothesis that K_V channels are electromechanically coupled to Ca_V1.2 channels and that coronary microvascular dysfunction in obesity is related to subsequent increases in Ca_V1.2 channel activity. Initial studies revealed that inhibition of K_V channels with 4-aminopyridine (4AP, 0.3 mM) increased intracellular [Ca²⁺], contracted isolated coronary arterioles and decreased coronary reactive hyperemia. These effects were reversed by blockade of Ca_V1.2 channels. Further studies in chronically instrumented Ossabaw swine showed that inhibition of Ca_V1.2 channels with nifedipine (10 μg/kg, iv) had no effect on coronary blood flow at rest or during exercise in lean swine. However, inhibition of Ca_V1.2 channels significantly increased coronary blood flow, conductance, and the balance between coronary flow and metabolism in obese swine (P < 0.05). These changes were associated with a ~50 % increase in inward Ca_V1.2 current and elevations in expression of the pore-forming subunit (α₁c) of Ca_V1.2 channels in coronary smooth muscle cells from obese swine. Taken together, these findings indicate that electromechanical coupling between K_V and Ca_V1.2 channels is involved in the regulation of coronary vasomotor tone and that increases in Ca_V1.2 channel activity contribute to coronary microvascular dysfunction in the setting of obesity.